Reduced pain hypersensitivity and inflammation in mice lacking microsomal prostaglandin E synthase-1

Daisuke Kamei, Kiyofumi Yamakawa, Yui Takegoshi, Maya Mikami-Nakanishi, Yoshihito Nakatani, Sachiko Oh-Ishi, Hidekazu Yasui, Yoshiaki Azuma, Noriyasu Hirasawa, Kazuo Ohuchi, Hiroshi Kawaguchi, Yukio Ishikawa, Toshiharu Ishii, Satoshi Uematsu, Shizuo Akira, Makoto Murakami, Ichiro Kudo

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Abstract

We examined the in vivo role of membrane-bound prostaglandin E synthase (mPGES)-1, a terminal enzyme in the PGE2-biosynthetic pathway, using mPGES-1 knockout (KO) mice. Comparison of PGES activity in the membrane fraction of tissues from mPGES-1 KO and wild-type (WT) mice indicated that mPGES-1 accounted for the majority of lipopolysaccharide (LPS)-inducible PGES in WT mice. LPS-stimulated production of PGE2, but not other PGs, was impaired markedly in mPGES-1-null macrophages, although a low level of cyclooxygenase-2-dependent PGE2 production still remained. Pain nociception, as assessed by the acetic acid writhing response, was reduced significantly in KO mice relative to WT mice. This phenotype was particularly evident when these mice were primed with LPS, where the stretching behavior and the peritoneal PGE2 level of KO mice were far less than those of WT mice. Formation of inflammatory granulation tissue and attendant angiogenesis in the dorsum induced by subcutaneous implantation of a cotton thread were reduced significantly in KO mice compared with WT mice. Moreover, collagen antibody-induced arthritis, a model for human rheumatoid arthritis, was milder in KO mice than in WT mice. Collectively, our present results provide unequivocal evidence that mPGES-1 contributes to the formation of PGE 2 involved in pain hypersensitivity and inflammation.

Original languageEnglish
Pages (from-to)33684-33695
Number of pages12
JournalJournal of Biological Chemistry
Volume279
Issue number32
DOIs
Publication statusPublished - 2004 Aug 6

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Kamei, D., Yamakawa, K., Takegoshi, Y., Mikami-Nakanishi, M., Nakatani, Y., Oh-Ishi, S., Yasui, H., Azuma, Y., Hirasawa, N., Ohuchi, K., Kawaguchi, H., Ishikawa, Y., Ishii, T., Uematsu, S., Akira, S., Murakami, M., & Kudo, I. (2004). Reduced pain hypersensitivity and inflammation in mice lacking microsomal prostaglandin E synthase-1. Journal of Biological Chemistry, 279(32), 33684-33695. https://doi.org/10.1074/jbc.M400199200